CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis

Prescription omega-3 fatty acid ethyl ester supplements are commonly used for the treatment of hypertriglyceridemia. However, the metabolic profile and effect of the metabolites formed by these treatments remain unknown. Here we utilized unbiased metabolomics to identify 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) as a significant metabolite of the omega-3-acid ethyl ester prescription Lovaza (TM) in humans. Administration of CMPF to mice before or after high-fat diet feeding at exposures equivalent to those observed in humans increased whole-body lipid metabolism, improved insulin sensitivity, increased beta-oxidation, reduced lipogenic gene expression, and ameliorated steatosis. Mechanistically, we find that CMPF acutely inhibits ACC activity, and induces long-termloss of SREBP1c and ACC1/2 expression. This corresponds to an induction of FGF21, which is required for long-term steatosis protection, as FGF21KO mice are refractory to the improved metabolic effects. Thus, CMPF treatment in mice parallels the effects of human Lovaza (TM) supplementation, revealing that CMPF may contribute to the improved metabolic effects observed with omega-3 fatty acid prescriptions. (c) 2017 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.